Apoptosis-based Therapies: Mechanisms and Applications
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1 Apoptosis-based Therapies: Mechanisms and Applications Perspective Bcl-2 family members, potential usage of BH3 domains as drug targets Bcl-2/xL inhibitors - Antisense, inhibitors of protein-protein interactions, SAR Caspases, apoptosome, inflammasome Caspase inhibitors and how they work TNFR, CD95/Fas, ApoL TRAIL and decoy receptors
2 Cell Death is a Physiological Response of Cells To Changes in the Extracellular Environment Differentiation Proliferation Cell Death (Apoptosis)
3 Historical Observations of Apoptosis in Development
4 Historical Timeline of Apoptosis Research
5 Diseases Associated with Defective Apoptosis Regulation I) Insufficient apoptosis Cancer (cell accumulation; resistance to chemotherapy, radiation and immunotherapy) Autoimmunity (failure to eliminate autoreactive lymphocytes) Restenosis (accumulation of vascular smooth muscle cells) Persistent infections (failure to eradicate bacteriaor virus-infected cells)
6 Diseases Associated with Defective Apoptosis Regulation II) Excessive apoptosis Ischemia reperfusion injury (stroke, myocardial infarction) Heart failure (myocyte loss) Neurodegeneration (Alzheimer s, Parkinson s, Huntington s and amyothrophic lateral sclerosis=als) Inflammation Osteoarthritis (chondrocyte depletion)
7 Diseases Associated with Defective Apoptosis Regulation II) Excessive apoptosis (cont d) HIV (depletion of T-lymphocytes) Bacterial infection using apoptosis-inducing virulence proteins Allograft rejection and graft versus host disease Type I diabetes Trauma (spinal cord injury, brain injury)
8 Oncology Targets Oncogenes (e.g., AKT, Bcl-2) Drugs Irradiation Stress Tumor suppressor genes (e.g., p53, PTEN, Caspases) Cell Death (Apoptosis)
9 The Core Cell Death Machinery
10 Mitochondria Conduct Apoptotic Signaling
11 Bcl-2 Proteins as Conserved Gatekeepers Of Mitochondrial Integrity
12 Death Signals Inhibit the Anti-Apoptotic Bcl-2 Family Member CED-9 in Lower Eukaryotes
13 Conservation of a Common Death Pathway Involving Bcl-2-Type Proteins
14 Bcl-2-Type Proteins are Characterized by a BH3 Domain of Protein-Protein Interactions
15 but Comprise a Family of Structurally and Functionally Diverse Proteins
16 Pro-Apoptotic Bcl-2 Family Members in Mammals Comprise Functionally Distinct Sentinels
17 That Sense Cellular Stress and are Activated by Multiple Mechanisms
18 Including Cleavage by Cellular Proteases BID (inactive) tbid (active)
19 Inhibition of Bcl-2/Bcl-x L Results in the Release of Apoptogenic Factors
20 Bcl-2/Bcl-x L as Drug Targets Antisense Oligonucleotides [e.g. Genta=G-3139 (5 -d(p-thio)tct-ccc-agc-gtg-ccc-cat-3 ) Natural Compounds (Antimycin A 3 binds to the hydrophobic groove in Bcl-x L and inhibits proteinprotein interactions) Small compounds (HA14.1 targeting Bcl-2) SAR by NMR = structure-activity relationships by nuclear magnetic resonance
21 Identification of HA14-1 by Computer Screening
22 SAR-by-NMR Method: Screening for Small Molecules and Improving their Affinities using Linkers and NMR
23 Advantage over Conventional Library Methods: Fewer Compounds have to be Synthesized
24 Sequence-Specific Proteases (Caspases) Execute Apoptotic Disassembly of Cellular Proteins
25 Caspases Contain Similar Catalytic Subunits And Distinct N-terminal Regulatory Domains
26 Initiator Caspases (Caspase-8,9) are Activated According to the Forced-Proximity-Model
27 Downstream of Death Signals (Caspase-8) Or Mitochondrial Damage (Caspase-9)
28 Executioner Caspases (Caspase-3,6,7) Form Structural Heterodimers
29 Executioner Caspases Require Processing by Upstream Proteases for Dimer Formation (=Activation)
30 Caspase-9 Differs from Other Caspases by Having Only a Single Active Site
31 that is Formed by the Induced Complex Formation of Caspase-9 Molecules
32 Apaf-1 Mediates the ATP/dATP- and Cytochrome c- Dependent Multimerization of Caspase-9
33 Electron Microscopy Photographs of Apaf-1 In Complex with datp and Cytochrome c
34 Apaf-1 Complexes (=Apoptosomes) Form Propeller Structures with Heptagonal Symmetry (=7-fold)
35 Components of the Apoptosome are Localized In Defined Parts of the Propeller Structure
36 Caspase-9 Molecules are Localized to the Hub And Form a Dome that is the Basis for the
37 Formation of the Evil Oreo of Apoptosis
38 Caspase Activity is Determined using Fluorogenic Tetrapeptides Resembling Protease Cleavage Sites
39 Systematical Permutations of Tetrapeptide Sequences Reveal Synthetic Substrate Peptides
40 With Increased Specificity for Selected Caspases And Groups of Caspases
41 That Form the Rational for the Generation of Peptoid Caspase Inhibitors Unfortunately: Limited Practical Use because of Hepatobiliar P 1 -Asp Transporter System (=Secretion)
42 In Summary: Death Receptor Signals (Extrinsic) Induce Caspase-8 Activation while
43 Cellular Stresses (Intrinsic) Cause Mitochondrial Damage Leading to Caspase-9 Activation
44 Other Caspases (Caspase-1,5) are Involved in Inflammatory Cell Responses
45 That Involve Multimolecular Complexes
46 And Lead to the Assembly of an Inflammasome
47 Extrinsic Cell Death Pathways Depend on Death-Receptor Ligands such as TRAIL
48 CD95/Fas/Apo1 Caspase-8 Activation (=Death)
49 Apo2L/TRAIL Caspase-8 Activation (=Death) Increased Sensitivity in Cancer Cells (Lack of Decoy Receptors)
50 Apo3L/TNF Caspase-8 Activation (=Death) + NF-κB Activation (=Survival) κ κ κ κ κ κ
51 Targeting the PI3K-Akt Pathway: Rationale and Promise Survival signaling by serine-threonine kinases (PTEN/PI3K/Akt) Akt functioning in metabolism, cell growth and survival Development of Akt inhibitors PI3K/Akt signaling as therapeutic target: ongoing clinical studies (CCI-778, RAD001) Outlook: DNA damage responses, p53
52 Cellular Receptors Transduce Extracellular Signals
53 Cellular Receptors Initiate Intracellular Cascades
54 PtdIns-Dependent Second Messengers Function In Distinct Intracellular Pathways
55 Depending on Distinct Regulatory Domains Of Target Proteins
56 PIP3-Dependent Cell Responses are Mediated by PTEN/PI3K/AKT
57 Sequence Alignment of AGC Kinases
58 Structure of Akt in Comparison with PKA
59 Structure of the N-terminal lobe
60 Role of αc Helix to Stabilize an Active Kinase State
61 Conservation of Hydrophobic Motif Binding Channel among AGC Kinases
62
63
64 PTEN/PI3K/AKT Signal Transduction is Evolutionarily Conserved
65 Loss of AKT Signaling Leads to Lifespan Extension and Reduced Cell Size (=Smaller Organisms) Yeast (sch9) Fly (Dakt) Mouse (Akt1,2,3)
66 Decreased Akt Gene Function = Mini-Mice Akt1 KO (~20% smaller) Akt1 wt Littermate
67 Multiple Cell Functions are Mediated by PTEN/PI3K/AKT
68 Increased Strength of AKT Signaling = Cancer
69 AKT Regulates Distinct and Conserved Protein Substrates
70 Including mtor and FoxO-type transcription factors
71 Lymphomagenesis as a Model of Clinical Cancer Treatement
72 Akt Promotes Chemoresistance in vivo
73 Rapamycin Reverses Akt-mediated Chemoresistance
74 Akt as Drug Targets PI3K Inhibitors (LY294002, wortmannin) mtor Inhibitors (rapamycin, CCI-778, RAD001) Natural plant compounds (curcumin, degeulin) do not inhibit PI3K but inhibit cancer cell proliferation 1L-6-hydroxy-methyl-chiro-inositol 2(R)-2-O-methyl-3-Ooctadecylcarbonate, D-3-deoxy-phosphatidyl-myo-inositol = PH domain targeting compounds Sequence-specific design of kinase inhibitors (Keryx Biopharmaceuticals) Azepan Derivatives (Roche) Fragment-based drug discovery (Astex) = Kinase domain targeting compounds
75 Outlook: DNA Damage Responses
76 Outlook: Role of p53
77
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